5-ht2a serotonin receptor inverse agonists or antagonists for use in reducing amyloid-beta peptides and accumulation of amyloid plaques

Abstract

Described are compounds and compositions for use in methods for reducing the rate of accumulation of amyloid plaques in a subject by administering a 5-HT2A serotonin receptor inverse agonist or antagonist, or pharmaceutically acceptable salts thereof.

1 .- 39 . (canceled) 
     
     
         40 . A method of delaying the onset of Alzheimer's disease by reducing the concentration of Aβ peptides (Aβ) in a subject in need thereof, wherein the concentration is in the brain of the subject, the method comprising administering to the subject an effective amount of a selective 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 40 , wherein, prior to being administered the 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof, the subject is identified by one or more of the following:
 amyloid plaque imaging using Positron Imaging Tomography (PET);   genetic testing for a mutation in the amyloid precursor protein (APP) gene;   genetic testing for a gene involved in processing amyloid precursor protein (APP);   genetic testing an apolipoprotein E (APOE) ε4 carrier;   genetic testing for trisomy for the amyloid precursor protein (APP) gene;   changes in amyloid biomarkers;   changes in tau biomarkers;   reduction from baseline in total whole brain, cortical or hippocampal volume;   increase in brain ventricular volume; and/or   the subject has mild cognitive impairment.   
     
     
         42 . The method of  claim 41 , wherein the tau or amyloid biomarkers are selected from the group consisting of total tau (t-tau) and phosphor-tau (p-tau), Aβ(1-40), Aβ(1-42), and Aβ(1-x) biomarkers. 
     
     
         43 . The method of  claim 41 , wherein the changes in amyloid biomarkers and tau biomarkers are in cerebrospinal fluid (CSF) or interstitial fluid (ISF) or plasma. 
     
     
         44 . The method of  claim 40 , wherein the subject has increased risk of developing Alzheimer's disease or dementia, wherein the increased risk of developing Alzheimer's disease or dementia is associated with diabetes, high blood pressure, obesity, smoking, depression, cognitive inactivity, low education, low physical inactivity, excessive alcohol intake, or subjects who experience severe or repeated head injuries. 
     
     
         45 . The method of  claim 40 , wherein the method further comprises identifying a subject to be administered the selective 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof, wherein the subject is identified by one or more of the following:
 detecting amyloid plaque imaging in the subject using Positron Imaging Tomography (PET);   determining by genetic testing that the subject has a mutation in the amyloid precursor protein (APP) gene;   detecting a mutation on chromosome 21, mutations on chromosome 14, or mutations on chromosome 1 involved in processing amyloid precursor protein (APP);   determining by genetic testing that the subject is an apolipoprotein E (APOE) ε4 carrier;   determining by genetic testing that the subject has a strong family history of Alzheimer's disease;   determining by genetic testing that the subject is trisomic for the amyloid precursor protein (APP) gene;   detecting changes in amyloid biomarkers in the subject;   detecting changes in tau biomarkers in the subject;   detecting reduction from baseline in total whole brain, cortical or hippocampal volume;   detecting increase in brain ventricular volume; and/or   determining the subject has mild cognitive impairment.   
     
     
         46 . The method of  claim 40 , wherein the 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of volinanserin, eplivanserin, pruvanserin, pimavanserin, glemanserin, nelotanserin, ITI-007, and Temanogrel. 
     
     
         47 . The method of  claim 40 , wherein the 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof is pimavanserin. 
     
     
         48 . The method of  claim 40 , wherein the subject is identified by amyloid plaque imaging using Positron Imaging Tomography (PET) of the brain of the subject, or the subject is identified by mutations on chromosome 21, mutations on chromosome 14, or mutations on chromosome 1. 
     
     
         49 . The method of  claim 40 , wherein the Aβ peptides are selected from the group consisting of Aβ38, Aβ40, Aβ42, and Aβ43. 
     
     
         50 . The method of  claim 40 , wherein the Aβ peptides are selected from Aβ40 and Aβ42. 
     
     
         51 . A method of delaying the onset of Alzheimer's disease by reducing the concentration of Aβ peptides (Aβ) in a subject in need thereof, wherein the concentration is in the brain of the subject, the method comprising administering to the subject an effective amount of a composition comprising a selective 5-HT2A serotonin receptor inverse agonist or antagonist or a pharmaceutically acceptable salt thereof, and an agent selected from the group consisting of: a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), an M1 muscarinic acetylcholine receptor agonist, a 5-HT4 serotonin receptor agonist, an anti-amyloid beta monoclonal antibody, and a beta-secretase 1 (BACE1) inhibitor. 
     
     
         52 . The method of  claim 51 , wherein the subject is identified by amyloid plaque imaging using Positron Imaging Tomography (PET) of the brain of the subject, or the subject is identified by mutations on chromosome 21, mutations on chromosome 14, or mutations on chromosome 1. 
     
     
         53 . The method of  claim 51 , wherein the Aβ peptides are selected from the group consisting of Aβ38, Aβ40, Aβ42, and Aβ43. 
     
     
         54 . The method of  claim 51 , wherein the Aβ peptides are selected from Aβ40 and Aβ42.